Peripheral artery disease (PAD) affects at least 12 million Americans annually, and half a million of them will require an endovascular or surgical revascularization procedure each year. Unfortunately, only one-third of patients have a patent artery one year after balloon angioplasty of the femoral artery. This rate has not significantly changed in the last 20 years highlighting a general deficit in mechanistic knowledge of failure and lack of adjunctive therapies. One possible reason for this has been the lack of imaging modalities capable of sub-millimeter resolution to assess in vivo serial changes in the vessel wall. Magnetic resonance imaging (MRI), with black-blood imaging techniques, now has sufficient spatial resolution to detect small changes in wall volumes and can be applied to serial in vivo studies. Further insights into the vascular wall can be provided with multi-contrast and dynamic-contrast imaging techniques, which are capable of providing information on vessel wall composition and perfusion arising from adventitial vasa vasorum. Recognizing that restenosis is a consequence of inflammation, we recently completed a Phase 1 study of delivering dexamethasone (DEX) to the adventitia via an endovascular micro-infusion catheter at the time of femoral artery angioplasty. The adventitia of an artery is an immune rich layer that actively participates in the vascular response to injury. This first-in-man study established the safety and feasibility of the local drug delivery method and provided excellent clinical outcomes. The fundamental hypothesis of this application is that inhibition of inflammation at the site of therap will result in improved vascular healing and a sustained patent artery. To address our hypothesis, we propose a randomized mechanistic trial to test whether DEX can improve the vascular healing response to angioplasty. In the first Specific Aim, MRI will be used to assess wall volume of the treated arterial segment in the drug compared to the control group. The vascular wall will be further characterized by measuring adventitial perfusion through kinetic modeling of contrast into the vessel wall from the plasma. This provides an estimate of tissue inflammation. Further we will employ computational fluid dynamics to assess hemodynamic descriptors and their interaction with treatment assignment on vascular remodeling. In Specific Aim #2, we will determine systemic inflammation at peri-operative time points and relate them to treatment assignment, vascular wall inflammation, and wall volume. In Specific Aim #3, we will determine femoral artery plaque composition (lipid rich necrotic core, calcification, and dense fibrous tissue) expressed as a percent of total wall volume of the treated segment. We will then determine each tissue type's relationship with the angioplasty outcomes, such as wall volume and remodeling, as well as the peri-procedural inflammatory response. Collectively, these specific aims will allow us to determine if patient-specific physiological parameters affect angioplasty outcomes, if DEX has a biological effect on the vascular wall, and if this effect is through the reduction of inflammation.